The present invention relates to delayed-release pharmaceutical compositions comprising an azole anti-fungal drug having poor water solubility, wherein the composition may be administered in either the fed or fasted state. Azole anti-fungal drugs having poor water solubility (e.g., including, but not limited to, itraconazole, posaconazole, voriconazole and terconazole) have been developed for treatment and/or prevention of fungal infections, including invasive fungal infections.
Posaconazole is a broad-spectrum triazole antifungal drug marketed under the tradename NOXAFIL® as a solution for injection, oral suspension, and gastro-resistant tablet for the treatment and prophylaxis of invasive fungal infections. NOXAFIL® is indicated for the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with a graft-versus-host-disease and patients with hematologic malignancies with prolonged neutropenia from chemotherapy. The oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC) as well.
Posaconazole has the chemical name of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, and has the structural formula (I):

Posaconazole free base has a solubility of approximately 0.8 mg/mL at gastric pH. However, when posaconazole dissolved in the gastric fluids reaches the environment of the intestines, which is less acidic (typically a pH of about 6.4), a substantial amount of the dissolved posaconazole precipitates, hindering absorption in the intestines. It has been determined that in environments where the pH is about pH 6.4 or higher, the solubility of posaconazole free base is less than about 1 μg/mL.
Bioavailability of posaconazole oral suspension (NOXAFIL®) is significantly enhanced when co-administered with food. For this reason, the oral suspension is administered during or immediately following a full meal to enhance the oral absorption of the drug. A delayed-release tablet formulation which releases posaconazole in the small intestine was developed to maximize systemic absorption and to overcome the food effect limitations of oral suspension formulations of posaconazole. However, commercially available posaconazole delayed-release tablets (NOXAFIL®) are only prescribed for use with food because of relatively poor bioavailability when administered under fasted conditions.
Itraconazole is a triazole antifungal drug used for the treatment of fungal infections, including superficial infections, such as onychomycosis, as well as systemic fungal infections, for example, pulmonary or extrapulmonary blastomycosis, histoplasmosis, and aspergillosis. Itraconazole has solubility of less than 1 μg/mL in water and 6 μg/mL in 0.1 N Hydrochloric acid. Itraconazole has the following structural Formula (II):
Commercially available solid oral dosage forms of itraconazole (SPORANOX®, ONMEL® and TOLSURA®) must be taken with food because bioavailability of itraconazole in these formulations is enhanced when administered under fed conditions.
Antifungal prophylaxis recipients routinely include two key populations: (i) patients with acute myelogenous leukaemia (AML), myelodysplastic syndrome (MDS), or other acute haematological malignancies, who may develop neutropenia and chemotherapy-induced side effects, namely, severe nausea or vomiting; and (ii) allogeneic hematopoietic stem cell transplant (HSCT) recipients, who routinely develop graft-versus-host disease (GVHD) and its associated complications, including severe mucositis or diarrhea. Adequate food intake to obtain optimal drug exposure may be difficult for these patients. Hence, there exists a need for improved oral pharmaceutical compositions for azole anti-fungal drugs that have poor water solubility, which also addresses the food effect.